i

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION 

EPA Registration Division contact: Sidney Jackson, (703) 305-7610

Docket I.D. Number: EPA-HQ-OPP-2014-0879

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: PP# 4E8330

EPA has received a pesticide petition (PP# 4E8330) from Interregional Research Project No. 4 

(IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540 requesting, pursuant 

to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 

346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of the 

herbicide, penoxsulam (2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4] triazolo[1,5-

c]pyrimidin-2-yl)-6-(trifluoromethyl)benzenesulfonamide) in/on the following raw 

agricultural commodities: Fruit, Pome, group 11-10 at 0.01 parts per million (ppm), Fruit, 

Stone, group 12-12 at 0.01 ppm, Fruit, Small, Vine Climbing, subgroup 13-07F, except 

Fuzzy Kiwifruit at 0.01 ppm, Nut, Tree, group 14-12 at 0.01 ppm, Olive at 0.01 ppm, and

Pomegranate at 0.01 ppm. In addition, the petitioner proposes based upon the 

establishment of the new tolerances above, removal of existing tolerances at 40 CFR 

180.605 for Grape at 0.01 ppm, Nut, tree, group 14 at 0.01 ppm and Pistachio at 0.01 

ppm. EPA has determined that the petition contains data or information regarding the 

elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully

evaluated the sufficiency of the submitted data at this time or whether the data support 

granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. Based on results of the metabolism studies in plants that are 

summarized below, it is concluded that the residue definition in plants is the parent 

compound alone, penoxsulam. 

A nature of residue study (NOR) was conducted in grapes using a soil application of 

penoxsulam. Penoxsulam, 14C-labeled either in the 2-position on the triazolopyrimidine 

ring (TP) or uniformly labeled in the phenyl-ring (Ph), was applied as a broadcast spray

onto soil around established grape vines at a single application rate of approximately 20 g 

a.i./ha. The soil in this study was a sandy clay loam. Application was made when grapes 

vines were at growth stage BBCH 55 (early flowering). After application, the plots were 

irrigated with 1 cm of water daily for 7 days. Grapes and leaves were harvested at 118 

days after application. 
2

Mature grapes contained residues below the limit of quantification (0.0008 μg/g 

penoxsulam equivalents). The PH-label and TP-label leaves collected at maturity

contained 0.016 μg/g and 0.013 μg/g penoxsulam equivalents, respectively. In the 

mature leaves, approximately 65% of the leaf TRR was extractable with neutral solvent, 

of which approximately half partitioned into organic solvent. The majority of the organic 

phase was identified as numerous low-level metabolites, while the aqueous phase 

consisted of primarily polar, solvent-front residues. The residue was characterized as 

low-level degradates, tentatively including the 5-hydroxy-penoxsulam and the dihydroxypenoxsulam metabolites.

In summary, very low levels of soil-applied penoxsulam and degradates are taken up by

the vine. No penoxsulam was detected in the leaves, and due to the low TRR levels in 

the grapes, no penoxsulam is predicted there either. The residue was characterized as 

low-level degradates, tentatively including the 5-hydroxy-penoxsulam and the dihydroxypenoxsulam metabolites.

Metabolism studies in livestock animals with 14C-labeled penoxsulam (2-position on the 

triazolopyrimidine ring or uniformly labeled in the phenyl ring) at a concentration 

equivalent to about 10 ppm in the diet indicated that approximately 99% of the 

administered dose was eliminated in the excreta. The low levels of residues (0.002-0.07 

ppm) in fat and edible tissues, milk or eggs demonstrate that residues due to penoxsulam 

would not accumulate in the animals. Additionally, the dose levels in these studies are 

about 200 to 1000 times higher than the theoretical maximum exposure in the animal diet 

of rice commodities treated with penoxsulam, therefore, livestock feeding studies are not 

considered necessary.

2. Analytical method. [In the Magnitude of Residue (MOR) studies conducted in 

Pome Fruit and Stone Fruit to support tolerances proposed in this petition, residues of 

penoxsulam were determined using the analytical method GRM 04.09. Residues of 

penoxsulam were extracted from the crop samples by homogenizing and shaking with an 

acetonitrile/water solution (80:20 v/v). An aliquot was diluted with 0.1N HCl and 

purified using a 96-well polymeric-reverse phase extraction (SPE) plate. The SPE plate 

was washed with a 40/60 methanol/water solution and eluted with acetonitrile into a 96-

well plate containing an acetonitrile/methanol/water mobile phase (15:15:70 containing 

0.1% acetic acid) and a stable isotope internal standard. The final solution was analyzed 

by liquid chromatography with positive-ion electrospray tandem mass spectrometry

(LC/MS/MS). The limit of detection (LOD) and limit of quantitation (LOQ) are 0.003 

μg/g and 0.010 μg/g, respectively.

3. Magnitude of residues. The proposed tolerances (Section F) are supported by

MOR studies in grapes, almonds and pecans conducted in the U.S. Trials were 

conducted in almonds and pecans to support a tolerance for the nut tree crop group (Nuts, 

tree, group 14) including pistachios, and almond hulls. Additionally, trials were 

conducted in grapes to support a tolerance for grapes.

B. Toxicological Profile
3

1. Acute toxicity. The acute toxicity of penoxsulam is considered low. The acute 

oral and dermal lethal dose (LD)50s were greater than 5000 milligram per kilogram 

(mg/kg), while the acute inhalation lethal concentration (LC)50 was greater than the 

highest attainable aerosol concentration (3.50 mg/L). Only very slight, transient dermal 

irritation was seen, and mild eye irritation was noted. Penoxsulam was negative for skin 

sensitization in a Magnussen and Kligman maximization test involving intradermal 

injection of penoxsulam with an adjuvant.

2. Genotoxicty. Penoxsulam was negative for genotoxicity when tested in in vitro

and in vivo systems.

3. Reproductive and developmental toxicity. Penoxsulam did not have any effect 

on reproductive parameters at dose levels that induced treatment-related effects in 

parental rats. At the highest dosage tested (300 mg/kg/day), body weights and weight 

gains in both males and females were depressed, liver and/or kidney weights were 

increased, and histologic changes were noted in the liver (males) and kidneys (females). 

At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic 

correlate, and histologic changes noted in the kidneys of females. Transient decreases in 

pup body weights were seen at the highest dosage tested, but dietary concentrations were 

targeted for adults and consumption of treated diets by the pups resulted in dose levels to 

the pups approximately 3-fold higher than in adults. A teratogenic potential was not 

demonstrated for penoxsulam in either rats or rabbits.

4. Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or 

urinary tract (kidneys and bladder) as target organs in rats, mice and dogs following 4-

week and 13-week administration. Effects on the liver were reflected in increased liver 

weights and hepatocellular hypertrophy, but these effects were not associated with 

increases in mixed function oxidase (MFO) enzyme activity. Effects noted in the kidneys 

included crystal deposition, most likely from precipitation of penoxsulam from the urine, 

with resultant irritation, inflammation and hyperplasia of renal pelvic transitional 

epithelium. Other than the crystal deposition in the kidneys, all effects following 

subchronic exposure to rats appeared to be reversible. Very high doses were associated 

with significant decreases in body weight and weight gain, and feed consumption.

5. Chronic toxicity. Chronic exposure in the dog indicated that the renal effects 

were not exacerbated with long-term exposure. Following long-term exposure in rats, the 

kidneys and urinary bladder were the primary target organs. Histologic changes seen at 

the end of 2-years of exposure consisted of inflammation and hyperplasia of the renal 

pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and 

hyperplasia of the mucosa of the urinary bladder. In the mouse, the liver was the primary

target organ, and histologic changes consisted of hepatocellular hypertrophy. There were 

no treatment-related increases in tumors in either rats or mice. The incidence of 

mononuclear cell leukemia (Fischer rat leukemia) was increased in all groups of treated 

male rats compared to the concurrent controls. However, the incidences in the treated 

groups were identical across a 50-fold increase in dosage, and well within the range of 

control values reported in the literature. Penoxsulam was classified as having “Suggestive 

Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic 
4

Potential”. EPA has concluded that cancer risk associated with penoxsulam is negligible.

6. Animal metabolism. Orally administered penoxsulam is rapidly absorbed, 

excreted and extensively metabolized in both male and female rats, thus, indicating that 

penoxsulam is not expected to accumulate in biological systems. The majority of the 

residue was associated with the parent, penoxsulam. Several metabolites were also 

observed but the vast majority were <1% of the administered dose. The major route of 

metabolism involves O-demethylation, producing the OH- Penoxsulam metabolite 

followed by conjugation.

7. Metabolite toxicology. A metabolism study with penoxsulam in rice revealed 

the presence of the parent, a desmethylation metabolite (5-OH- Penoxsulam), and two 

other polar metabolites, which may represent conjugates of the desmethylated metabolite. 

The 5-OH-Penoxsulam metabolite and its glucuronide and glutathione conjugates have 

also been identified in the plasma and liver of rats, therefore, plant metabolites are 

considered of little toxicological concern.

8. Endocrine disruption. Penoxsulam did not have any effects on endocrine 

organs or tissues in mice, rats or dogs in any of the studies conducted. There were no 

indications of effects on fetal development in either rats or rabbits, or on reproductive 

performance in rats. Based on the lack of any effects on the endocrine system, 

penoxsulam is not considered an endocrine disrupter.

C. Aggregate Exposure

1. Dietary exposure. Tier 1 dietary risk assessments were performed using Dietary

Exposure Evaluation Model software with the Food Commodity Intake Database 

(DEEM-FCIDTM) software (version 3.14) to determine consumption of Fruits, Pome 

group 11-10, and Fruits, Stone group 12-12, Fruit, Small, Vine Climbing, Subgroup 13-

07F, except Kiwifruit, olive and pomegranate containing penoxsulam residues and to 

determine dietary exposure resulting from consumption of Fruits, Pome group 11-10, and 

Fruits, Stone group 12-12, Fruit, Small, Vine Climbing, Subgroup 13-07F, except 

Kiwifruit, Olive and Pomegranate treated with penoxsulam.

i. Food. Penoxsulam is registered for use as an herbicide on rice. Therefore, 

consumption of rice that has been treated with penoxsulam could result in dietary

exposures. On September 24, 2004, EPA finalized tolerances for penoxsulam in rice, 

grain (0.02 ppm) and rice, straw (0.5 ppm) (69 FR 57188-57197). In establishing the 

tolerances for rice, grain and rice, straw, EPA concluded that chronic dietary exposures 

were <1% of the chronic population adjusted dose (cPAD), but exposure estimates were 

not provided. On July 25, 2007, EPA finalized tolerances for penoxsulam in fish, and 

shellfish. On April 24, 2009 EPA finalized tolerances for penoxsulam in or on almond 

hulls; grape; nut, tree, group 14; and pistachio. For the purposes of this aggregate 

assessment, it is necessary to estimate dietary exposures of penoxsulam resulting from 

tolerance level residues on rice, fish and shellfish, almond hulls; grape; nut, tree, group 

14; and pistachio in addition to the proposed new uses. Secondary residues in meat, milk 

and poultry were not included because the transferability of penoxsulam to edible tissues 
5

is quite low and tolerances are not required. A chronic dietary exposure and risk 

assessment for tolerance-level residues in existing and proposed uses was performed 

using the DEEM-FCIDTM software (version 3.14). An acute dietary assessment was not 

performed because no toxicity endpoint has been identified to evaluate acute dietary

exposures to penoxsulam (EPA, 2004). To produce a conservative Tier 1 dietary risk 

assessment, tolerance-level residues were assumed for all commodities, and 100 percent 

crop treated was assumed for all commodities. Dietary penoxsulam exposures are low, 

accounting for less than 6% of the cRfD (0.147 mg/kg/d) for all subpopulations.

ii. Drinking water. The estimated drinking water concentrations (EDWCs) for the 

herbicide penoxsulam in groundwater and surface water resulting from ground spray

applications in Tree crops have been calculated according to EPA guidance. For 

groundwater, EDWCs were derived using the Screening Concentration in Ground Water 

(SCI-GROW) and Pesticide Root Zone Model-Ground Water (PRZM-GW) models. For 

surface water, the PRZM- Exposure Analysis Modeling System (EXAMS) model was 

used. The values generated were lower than the conservative values generated for aquatic 

weed control. For the purpose of these assessments, 150 ppb was used for the chronic 

exposure estimate for water, and this value was incorporated as a single point estimate for 

both “water, direct, all sources” and “water, indirect, all sources” within DEEM-FCIDTM

food categories exposure modeling. Based on the conservative assumptions used and 

using a cPAD of 0.147 mg/kg/day, the chronic dietary exposure to penoxsulam from all 

registered and proposed uses and drinking water, to all population subgroups is 

approximately <6% of the cPAD. All Infants have been identified as the most highly

exposed population subgroup yet utilizing only <6% of the cPAD.

2. Non-dietary exposure. The residential exposure portion of the risk assessment 

has been updated using current EPA practices. The proposed changes do not impact the 

previous human health assessment conclusion for penoxsulam in which it was determined 

that the percentages of chronic population adjusted dose for all population subgroups 

were less than 100% and therefore do not exceed the Agency’s level of concern. The 

change in the dietary contribution and the estimated residential exposures also do not 

change the conclusions of the previous assessment regarding Short-Term and 

Intermediate-Term exposures; aggregate margin of exposures (MOEs) remain acceptable. 

Thus, anticipated aggregate exposures estimated with conservative assumptions regarding 

use patterns of the full range of registered and proposed penoxsulam products are not of 

concern.

D. Cumulative Effects

Currently no common mechanism of toxicity has been found between penoxsulam 

and any other substances EPA and penoxsulam does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, it is

not assumed that penoxsulam has a common mechanism of toxicity with other

substances.

E. Safety Determination
6

1. U.S. population. Using the conservative exposure assumptions described above, 

and based on the completeness and reliability of the toxicity data, the aggregate exposure 

to penoxsulam, as determined under the guidance of the FQPA, will utilize less than 6% 

of the RfD from the dietary exposure for all subgroups of the U.S. population. Generally

and under the FQPA, the U.S. EPA has no concern for exposures below 100% of the RfD 

because the RfD represents the level at or below which daily dietary exposure over a 

lifetime will not pose appreciable risks to human health. Additionally, the chronic 

dietary exposure to penoxsulam from all registered and proposed uses and drinking 

water, to all population subgroups is approximately 6% of the cPAD. Therefore, there is 

a reasonable certainty that no harm will result to the general U.S. population from 

aggregate exposure to penoxsulam residues from the proposed use.

2. Infants and children. In assessing the potential for additional sensitivity of 

infants and children to residues of penoxsulam, data from developmental toxicity studies 

in rats and rabbits and a multi-generation reproduction study in the rat are considered. 

The developmental toxicity studies are designed to evaluate adverse effects on the 

developing organism resulting from pesticide exposure during prenatal development. 

Reproduction studies provide information relating to effects from exposure of both 

parents to the pesticide on the reproductive capability and potential systemic toxicity of 

mating animals and on various parameters associated with the well being of offspring.

FFDCA section 408 provides that the U.S. EPA may apply an additional safety factor for 

infants and children in the case of threshold effects to account for pre- and post-natal 

toxicity and the completeness of the database. Based on the current toxicological data 

requirements, the database for penoxsulam relative to pre- and post-natal effects for 

children is complete. Overall, penoxsulam had no effect on reproduction or embryo-fetal 

development at any dosage tested. No quantitative or qualitative susceptibility was seen 

following pre- and post-natal exposures. In a rabbit developmental toxicity study, effects 

on in-utero survival were observed only at a dose level where clear maternal toxicity was 

seen. In a 2-generation reproductive toxicity study in rats, no effects on reproductive 

performance were observed and effects on neonatal growth were seen only at a dose level 

where parental toxicity was seen. In addition, the no-observed adverse effect level

(NOAEL) in the chronic dog study (14.7 mg/kg/day), used to calculate the chronic

reference dose (RfD) (0.147 mg/kg/day), is already lower than the NOAEL from the 

rabbit developmental study (25 mg/kg/day). Therefore, an additional FQPA uncertainty 

factor is not needed and the RfD at 0.147 mg/kg/day is appropriate for assessing risk to 

infants and children. Using the conservative exposure assumptions previously described, 

the percent RfD utilized by the potential exposure to residues of penoxsulam is less than 

6% for the population subgroup predicted to be potentially the most highly exposed. 

Based on the aggregate exposure to penoxsulam, Dow AgroSciences concludes with 

reasonable certainty that no harm will result to infants and children, females 13+ years 

old and the prenatal development of infants.

F. International Tolerances

A review of Maximum Residue Limits (MRLs) established globally indicates that 
7

MRLs of 0.01 have been established in Japan for penoxsulam in or on Pome Fruit, Stone 

Fruit, grapes, Almond, and Pecan.